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Design, synthesis and biological evaluation of novel 1H-1,2,4-triazole, benzothiazole and indazole-based derivatives as potent FGFR1 inhibitors viafragment-based virtual screening
- Source :
- Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 72-84 (2020)
- Publication Year :
- 2020
- Publisher :
- Taylor & Francis Group, 2020.
-
Abstract
- Fibroblast growth-factor receptor (FGFR) is a potential target for cancer therapy. We designed three novel series of FGFR1 inhibitors bearing indazole, benzothiazole, and 1H-1,2,4-triazole scaffold via fragment-based virtual screening. All the newly synthesised compounds were evaluated in vitro for their inhibitory activities against FGFR1. Compound 9d bearing an indazole scaffold was first identified as a hit compound, with excellent kinase inhibitory activity (IC50 = 15.0 nM) and modest anti-proliferative activity (IC50 = 785.8 nM). Through two rounds of optimisation, the indazole derivative 9 u stood out as the most potent FGFR1 inhibitors with the best enzyme inhibitory activity (IC50 = 3.3 nM) and cellular activity (IC50 = 468.2 nM). Moreover, 9 u also exhibited good kinase selectivity. In addition, molecular docking study was performed to investigate the binding mode between target compounds and FGFR1.
- Subjects :
- Pharmacology
fgfr1
Indazole
Virtual screening
010405 organic chemistry
Kinase
1,2,4-Triazole
General Medicine
RM1-950
anticancer
01 natural sciences
Combinatorial chemistry
In vitro
0104 chemical sciences
010404 medicinal & biomolecular chemistry
chemistry.chemical_compound
chemistry
Benzothiazole
Fibroblast growth factor receptor
Drug Discovery
Therapeutics. Pharmacology
IC50
fgfr1 inhibitor
fragment-based virtual screening
Subjects
Details
- Language :
- English
- ISSN :
- 14756374 and 14756366
- Volume :
- 35
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....616b6d0b4fcc3c0fc1bb3278213daceb